U.S. patent number 10,576,121 [Application Number 15/514,476] was granted by the patent office on 2020-03-03 for composition and method for the treatment of menopause.
This patent grant is currently assigned to Mary Tagliaferri. The grantee listed for this patent is Mary Tagliaferri. Invention is credited to Mary Tagliaferri.
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United States Patent |
10,576,121 |
Tagliaferri |
March 3, 2020 |
Composition and method for the treatment of menopause
Abstract
Provided herein are compositions comprising an herbal extract of
a mixture of Radix Rehmanniae, Fructus Corni Officinalis, Radix
Dioscoreae Oppositae, Sclerotium Poriae Cocos, Cortex Moutan
Radicis, Rhizoma Alismatis Orientalis, Anemarrhena Rhizome,
Glycyrrhiza uralensis, Radix Astragali, and Atractylodis
Macrocephalae Rhizoma. The invention also relates to a method of
treating hot flashes associated with peri-menopause, menopause, or
post-menopause, a method of reducing total cholesterol and/or
lowering low density lipoprotein (LDL) levels and a method of
reducing weight and/or body mass index (BM I) using the above
mentioned herbal extract.
Inventors: |
Tagliaferri; Mary (San Anselmo,
CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Tagliaferri; Mary |
San Anselmo |
CA |
US |
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Assignee: |
Tagliaferri; Mary (San Anselmo,
CA)
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Family
ID: |
54261133 |
Appl.
No.: |
15/514,476 |
Filed: |
September 25, 2015 |
PCT
Filed: |
September 25, 2015 |
PCT No.: |
PCT/US2015/052417 |
371(c)(1),(2),(4) Date: |
March 24, 2017 |
PCT
Pub. No.: |
WO2016/049561 |
PCT
Pub. Date: |
March 31, 2016 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20170281707 A1 |
Oct 5, 2017 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62056370 |
Sep 26, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
36/076 (20130101); A61K 36/884 (20130101); A61K
36/484 (20130101); A61K 36/8945 (20130101); A61P
5/30 (20180101); A61K 9/19 (20130101); A61K
9/16 (20130101); A61K 36/65 (20130101); A61K
36/40 (20130101); A61P 3/04 (20180101); A61K
9/148 (20130101); A61K 36/481 (20130101); A61K
36/8964 (20130101); A61P 3/06 (20180101); A61K
36/804 (20130101); A61K 36/284 (20130101) |
Current International
Class: |
A61K
36/8945 (20060101); A61K 9/19 (20060101); A61K
9/16 (20060101); A61K 9/14 (20060101); A61K
36/40 (20060101); A61K 36/284 (20060101); A61K
36/076 (20060101); A61K 36/884 (20060101); A61K
36/8964 (20060101); A61K 36/804 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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104524337 |
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Apr 2015 |
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CN |
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WO 2016/049561 |
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Mar 2016 |
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WO |
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Other References
Jacobs, et al., Integrative Cancer Therapies, 2:289. (Year: 2003).
cited by examiner .
Giovanni Maciocia, "The Treatment of Menopausal Problems,"
(http://maciociaonline.blogspot.com/2012/09/the-treatment-of-menopausal-p-
roblems.html). (Year: 2012). cited by examiner .
Chen et al., "Use of Chinese herbal medicine among menopausal women
in Taiwan", Int. J. Gynecol. Obstet., vol. 109, No. 1, pp. 63-66
(2010). cited by applicant .
Chen et al., "Prescription patterns of Chinese herbal products for
menopausal syndrome: analysis of a nationwide prescription
database", J. Ethnopharmacol., vol. 137, No. 3, pp. 1261-1266
(2011). cited by applicant .
Dharmananda, "The treatment of menopausal syndrome with Chinese
herbs", Online article retrieved from the internet from:
http://www.itmonline.org/arts/menopaus.htm, 10 pages (Mar. 1999).
cited by applicant .
Gold et al., "Longitudinal analysis of the association between
vasomotor symptoms and race/ethnicity across the menopausal
transition: study of women's health across the nation", Am. J.
Public Health., vol. 96, No. 7, pp. 1226-1235 (2006). cited by
applicant .
Grady, "Clinical practice. Management of menopausal symptoms", N.
Engl. J. Med., vol. 355, No. 22, pp. 2338-2347 (2006). cited by
applicant .
International Search Report from PCT Patent Application No.
PCT/US2015/052417 dated Nov. 13, 2015, application now published as
International Publication No. WO2016/049561 dated Mar. 31, 2016.
cited by applicant .
Nelson et al., "Management of menopause-related symptoms", Evidence
Report/Technology Assessment, No. 120, AHRQ Publication No.
05-E016-2, 916 pages (2005). cited by applicant .
Rossouw et al., "Risks and benefits of estrogen plus progestin in
healthy postmenopausal women: principal results From the Women's
Health Initiative randomized controlled trial", JAMA, vol. 288, No.
3, pp. 321-333 (2002). cited by applicant .
Stearns et al., "Hot flushes", Lancet., vol. 360, No. 9348, pp.
1851-1861 (2002). cited by applicant.
|
Primary Examiner: Barker; Michael
Attorney, Agent or Firm: McDermott Will & Emery LLP
Mohr; Judy M. Li; Wen
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a U.S. National Stage of International Patent
Application No. PCT/US2015/052417, filed Sep. 25, 2015, which
claims the benefit of priority to U.S. Provisional Application No.
62/056,370, filed Sep. 26, 2014, each of which is incorporated
herein by reference in its entirety.
Claims
What is claimed is:
1. A method of treating hot flashes associated with peri-menopause,
menopause, or post-menopause, comprising: administering a
therapeutically effective amount of a composition consisting
essentially of herbal extracts of 5-20 wt % Radix Rehmanniae , 5-20
wt % Fructus Corni Officinalis, 5-20 wt % Radix Dioscoreae
Oppositae, 5-15 wt % Sclerotium Poriae Cocos, 5-15 wt % Cortex
Moutan Radicis, 5-15 wt % Rhizoma Alismatis Orientalis, 5-15 wt %
Anemarrhena Rhizome, 5-15 wt % Glycyrrhiza uralensis, 2-10 wt %
Radix Astragali, and 5-15 wt % Atractylodis Macrocephalae
Rhizoma.
2. The method of claim 1, wherein said administering reduces at
least one of the frequency, the duration, the severity, the number
of nighttime awakenings, or the number of hot flashes per day.
3. The method of claim 1, wherein the composition is administered
as a dose of 500-4000 mg of the combined herbal extracts per
day.
4. The method of claim 1, wherein about 0.1-10 mg/kg of the
composition is administered daily.
5. The method of claim 1, wherein the composition is administered
for a period of about 4-52 weeks.
6. The method of claim 1, wherein the composition is administered
about 30 minutes after a meal.
7. The method of claim 1, wherein administration of the composition
selectively activates ER.beta..
Description
TECHNICAL FIELD
The disclosure relates generally to a composition, and method for
treating menopause, or the symptoms thereof, and related features
thereof.
BACKGROUND
Vasomotor symptoms are reported by 60-80% of menopausal women (Gold
et al., Am J Public Health, 2006, 96:1226-35) and approximately
one-third of this population reports symptoms severe enough to seek
treatment (Stearns et al., Lancet, 2002, 360:1851-1861). Vasomotor
symptoms include hot flashes, hot flushes, and night sweats. Hot
flashes are manifested as in increase in skin temperature and are
often accompanied by a sudden onset of sweating on the face, neck
and/or chest. Hot flashes and other vasomotor symptoms are
commonly, but not exclusively, associated with females in a
perimenopausal, menopausal or postmenopausal state.
The currently preferred treatment for menopausal symptoms,
including vasomotor symptoms, is hormone replacement therapy using
either estrogen or an estrogen/progesterone combination. While
estrogens are an effective treatment for vasomotor symptoms (Nelson
et al., AHRQ Publication No. 05-E016-2, 2005), concerns have been
raised about the increased risk of uterine cancer, breast cancer
and cardiovascular events associated with use of estrogen-based
postmenopausal hormone therapy. Estrogen therapy is also
contraindicated in patients previously diagnosed with breast cancer
as estrogen and progesterone may be associated with an increased
risk of cancer recurrence and are known to specifically promote
growth of breast cancer cell with estrogen receptors. The use of
selective serotonin reuptake inhibitors have shown modest efficacy
in the treatment of hot flashes but have side effects that limit
their use (Grady, N Engl J Med, 2006, 355:2338-47).
There are also numerous non-hormonal remedies commonly used by
women suffering hot flashes including, for example, isoflavone,
black cohosh, vitamin E, and the antidepressants fluoxetine,
paroxetine, and venlafaxine. However, efficacy of these remedies is
less than that of the hormone replacement therapies. A clinical
trial with the plant-derived ER.beta.-selective extract, MF101
found a significant reduction of hot flashes in postmenopausal
women (see U.S. Pat. No. 7,482,029).
Thus, there is a need for therapeutic compositions and methods for
the treatment of the symptoms of perimenopause, menopause and/or
postmenopause including hot flashes. There is a particular need for
therapeutic compositions for the treatment or amelioration of
menopausal symptoms that does not promote or increase the risk of
cancers including breast cancer and uterine cancer.
BRIEF SUMMARY
The following aspects and embodiments described and illustrated
below are meant to be exemplary and illustrative, and are no way
intended to be limiting in scope.
In a first aspect, provided is a composition comprising or
consisting essentially of herbal extracts of Radix Rehmanniae,
Fructus Corni Officinalis, Radix Dioscoreae Oppositae, Sclerotium
Poriae Cocos, Cortex Moutan Radicis, Rhizoma Alismatis Orientalis,
Anemarrhena Rhizome, Glycyrrhiza uralensis, Radix Astragali, and
Atractylodis Macrocephalae Rhizoma. In one embodiment, the herbal
extracts are present as about 12% Radix Rehmanniae, about 12%
Fructus Corni Officinalis, about 12% Radix Dioscoreae Oppositae,
about 10% Sclerotium Poriae Cocos, about 10% Cortex Moutan Radicis,
about 10% Rhizoma Alismatis Orientalis, about 10% Anemarrhena
Rhizome, about 10% Glycyrrhiza uralensis, about 6% Radix Astragali,
and about 8% Atractylodis Macrocephalae Rhizoma. In some
embodiments, at least some of the herbal extracts are aqueous
extracts. In some embodiments, at least some of the herbal extracts
are formulated in one or more oils. In some embodiments, the oil is
one or more vegetable oils. In some specific embodiments, the oil
is canola oil, olive oil, soybean oil, sunflower seed oil, peanut
oil, palm oil, corn oil, sesame oil, and/or coconut oil. In a
further embodiment, the composition is formulated as a spray-dried
powder or a freeze-dried powder. In other embodiments, the
composition is formulated as a capsule or tablet.
In another aspect, compositions are provided for use in treating,
preventing, or ameliorating one or more symptoms of peri-menopause,
menopause, and or post-menopause. In an embodiment, the composition
is for use in treating, preventing, or ameliorating hot flashes. In
another aspect, compositions are provided for use in reducing total
cholesterol and/or lowering or reducing low density lipoprotein
levels. In another aspect, compositions are provided for use in
reducing weight and/or lowering a subject's body mass index. In
some embodiments, a dose of about 500-4000 mg of the combined
herbal extracts is administered daily, weekly, or monthly. In some
embodiments, about 0.1-10 mg/kg of the composition is administered
daily, weekly, or monthly. In some embodiments, the composition is
administered for a period of about 4-52 weeks or more. In one
embodiment, the composition is administered about 30-60 minutes
after a meal.
Additional embodiments of the present compositions, methods, and
the like, will be apparent from the following description,
drawings, examples, and claims. As can be appreciated from the
foregoing and following description, each and every feature
described herein, and each and every combination of two or more of
such features, is included within the scope of the present
disclosure provided that the features included in such a
combination are not mutually inconsistent. In addition, any feature
or combination of features may be specifically excluded from any
embodiment of the present invention.
Additional aspects and advantages of the present invention are set
forth in the following description and claims, particularly when
considered in conjunction with the accompanying examples and
drawings.
BRIEF DESCRIPTION OF DRAWINGS
FIGS. 1A-1B are bar graphs comparing the activity of the
composition to estradiol (E.sub.2) and a control on ER.alpha. and
ER.beta. expressing cells. FIG. 1A shows the effect of the
composition at 10, 25, 50, or 100 .mu.g/ml, a control, and E.sub.2
on ER.alpha. expressing cells as measured by luciferase activity in
relative light units (RLU). FIG. 1B compares the effect of the
composition at 10, 25, 50, or 100 .mu.g/ml, a control, and E.sub.2
on ER.beta. expressing cells as measured by luciferase activity in
relative light units (RLU).
FIG. 2 is a line graph showing the reduction in moderate to severe
hot flashes after administration of the composition. The graph
shows the median percent change in moderate to severe hot flashes
over 12 weeks of treatment from a baseline.
FIG. 3 is a line graph showing the reduction in awakenings from
sleep due to hot flashes after administration of the composition.
The graph shows the median percent change in awakenings from sleep
over 12 weeks of treatment from a baseline.
DETAILED DESCRIPTION
Various aspects of the compositions and related methods will be
described more fully hereinafter. Such aspects may, however, be
embodied in many different forms and should not be construed as
limited to the embodiments set forth herein; rather, these
embodiments are provided so that this disclosure will be thorough
and complete, and will fully convey its scope to those skilled in
the art.
The practice of the present disclosure will employ, unless
otherwise indicated, conventional methods of chemistry,
biochemistry, and pharmacology, within the skill of the art. Such
techniques are explained fully in the literature. See, e.g.; A. L.
Lehninger, Biochemistry (Worth Publishers, Inc., current addition);
Morrison and Boyd, Organic Chemistry (Allyn and Bacon, Inc.,
current addition); J. March, Advanced Organic Chemistry (McGraw
Hill, current addition); Remington: The Science and Practice of
Pharmacy, A. Gennaro, Ed., 20.sup.th Ed.; Goodman & Gilman The
Pharmacological Basis of Therapeutics, J. Griffith Hardman, L. L.
Limbird, A. Gilman, 10.sup.th Ed.
Where a range of values is provided, it is intended that each
intervening value between the upper and lower limit of that range
and any other stated or intervening value in that stated range is
encompassed within the disclosure. For example, if a range of 1
.mu.g to 5 .mu.g is stated, it is intended that 2 .mu.g, 3 .mu.g, 4
.mu.g, and 5 .mu.g are also explicitly disclosed, as well as the
range of values greater than or equal to 1 .mu.g and the range of
values less than or equal to 5 .mu.g.
I. DEFINITIONS
As used in this specification, the singular forms "a," "an," and
"the" include plural referents unless the context clearly dictates
otherwise. Thus, for example, reference to a "polymer" includes a
single polymer as well as two or more of the same or different
polymers, reference to an "excipient" includes a single excipient
as well as two or more of the same or different excipients, and the
like.
In describing and claiming the present invention, the following
terminology will be used in accordance with the definitions
described below.
An "herbal extract" as used herein refers generally to substance
that is obtained by extracting a portion of an herb, usually by use
of a solvent.
As used herein, "menopause" or "menopausal" includes perimenopause,
menopause, and post-menopause.
"Optional" or "optionally" means that the subsequently described
circumstance may or may not occur, so that the description includes
instances where the circumstance occurs and instances where it does
not.
"Substantially" or "essentially" means nearly totally or
completely, for instance, 90% or greater of some given
quantity.
II. OVERVIEW
The present disclosure is directed, at least in part, to the
discovery of composition comprising extracts from ten botanical
agents that acts as a selective estrogen receptor beta agonist and
is useful for the treatment of the symptoms of peri-menopause,
menopause, and post-menopause. The present disclosure is further
directed to the discovery of the composition for use in lowering
total cholesterol and/or low density lipoproteins. The present
disclosure is also directed to the discovery of the composition for
use in lowering a subject's weight and/or body mass index
(BMI).
III. COMPOSITION
Estrogen signaling pathways are mediated by the estrogen receptor
.alpha. (ER.alpha.) and estrogen receptor .beta. (ER.beta.)
estrogen receptors. Studies have suggested that drugs selectively
targeted to the ER.alpha. or the ER.beta. estrogen receptor may
produce more selective clinical effects. However, studies have
shown that the proliferative effects on endometrial and breast
cells associated with hormone replacement therapy are mediated by
ER.alpha.. Thus, the adverse effects associated with hormone
replacement therapy may be due to activation of ER.alpha.. The
present compositions selectively activate the estrogen response
element (ERE) with ER.beta..
The present compositions include a mixture of herbal extracts of
Radix Rehmanniae, Fructus Corni Officinalis, Radix Dioscoreae
Oppositae, Sclerotium Poriae Cocos, Cortex Moutan Radicis, Rhizoma
Alismatis Orientalis, Anemarrhena Rhizome, Glycyrrhiza uralensis,
Radix Astragali, and Atractylodis Macrocephalae Rhizoma. It will be
appreciated that, in general, the composition includes herbal
mixtures, extracts of herbal mixtures and mixtures of herbal
extracts. In some embodiments, the composition comprises, consists
essentially of, or consists of a mixture of the herbs or a mixture
of herbal extracts in accord with Table 1:
TABLE-US-00001 TABLE 1 Exemplary Formulation Herbal Ingredient
Percent by weight Weight in mg Radix Rehmanniae 5-20% 30-600
Fructus Corni Officinalis 5-20% 30-600 Radix Dioscoreae Oppositae
5-20% 30-600 Sclerotium Poriae Cocos 5-15% 25-500 Cortex Moutan
Radicis 5-15% 25-500 Rhizoma Alismatis Orientalis 5-15% 25-500
Anemarrhena Rhizome 5-15% 25-500 Glycyrrhiza uralensis 5-15% 25-500
Radix Astragali 2-10% 15-300 Atractylodis Macrocephalae 5-15.sup.
20-400 Rhizoma
It will be appreciated that the percent by weight as described in
Table 1 may refer to the percent by weight of the total composition
weight or the percent by weight of the herbal ingredients. It will
be appreciated that any or all of the herbs may be used in the
composition including, but not limited to, the flower, fruit,
leaves, stem, bark and/or roots as appropriate.
In embodiments, the formulation comprises about 30-600 mg, about
30-550 mg, about 30-500 mg, about 30-450 mg, about 30-400 mg, about
30-350, about 30-300, about 30-250, about 30-200, about 30-150,
about 30-120, about 30-100, about 30-60, about 30-50, about 50-600
mg, about 50-550 mg, about 50-500 mg, about 50-450 mg, about 50-400
mg, about 50-350, about 50-300, about 50-250, about 50-200, about
50-150, about 50-120, about 50-100, about 50-60, about 60-600 mg,
about 60-550 mg, about 60-500 mg, about 60-450 mg, about 60-400 mg,
about 60-350, about 60-300, about 60-250, about 60-200, about
60-150, about 60-120, about 60-100, about 100-600 mg, about 100-550
mg, about 100-500 mg, about 100-450 mg, about 100-400 mg, about
100-350, about 100-300, about 100-250, about 100-200, about
100-150, about 100-120, about 120-600 mg, about 120-550 mg, about
120-500 mg, about 120-450 mg, about 120-400 mg, about 120-350,
about 120-300, about 120-250, about 120-200, about 120-150, about
150-600 mg, about 150-550 mg, about 150-500 mg, about 150-450 mg,
about 150-400 mg, about 150-350, about 150-300, about 150-250,
about 150-200, about 200-600 mg, about 200-550 mg, about 200-500
mg, about 200-450 mg, about 200-400 mg, about 200-350, about
200-300, about 200-250, about 250-600 mg, about 250-550 mg, about
250-500 mg, about 250-450 mg, about 250-400 mg, about 250-350,
about 250-300, about 300-600 mg, about 300-550 mg, about 300-500
mg, about 300-450 mg, about 300-400 mg, about 300-350, about
350-600 mg, about 350-550 mg, about 350-500 mg, about 350-450 mg,
about 350-400 mg, about 400-600 mg, about 400-550 mg, about 400-500
mg, about 400-450 mg, about 450-600 mg, about 450-550 mg, about
450-500 mg, about 500-600 mg, about 500-550 mg, or about 550-600 mg
of one or more of Radix Rehmanniae, Fructus Corni Officinalis,
and/or Radix Dioscoreae Oppositae. In specific embodiments, the
formulation comprises about 30 mg, about 40 mg, about 50 mg, about
60 mg, about 100 mg, about 120 mg, about 150 mg, about 180 mg,
about 200 mg, about 240 mg, about 250 mg, about 300 mg, about 350
mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about
480 mg, about 500 mg, about 540 mg, about 550 mg, or about 600 mg
of one or more of Radix Rehmanniae, Fructus Corni Officinalis,
and/or Radix Dioscoreae Oppositae. It will be appreciated that the
amounts above may refer to the amount per capsule or the amount per
daily, weekly or monthly dose.
In other embodiments, the formulation comprises about 25-500 mg,
about 25-450 mg, about 25-400 mg, about 25-350, about 25-300, about
25-250, about 25-200, about 25-150, about 25-100, about 25-50,
about 50-500 mg, about 50-450 mg, about 50-400 mg, about 50-350,
about 50-300, about 50-250, about 50-200, about 50-150, about
50-100, about 75-500 mg, about 75-550 mg, about 75-500 mg, about
75-450 mg, about 75-400 mg, about 75-350, about 75-300, about
75-250, about 75-200, about 75-150, about 75-100, about 100-500 mg,
about 100-450 mg, about 100-400 mg, about 100-350, about 100-300,
about 100-250, about 100-200, about 100-150, about 150-500 mg,
about 150-450 mg, about 150-400 mg, about 150-350, about 150-300,
about 150-250, about 150-200, about 200-500 mg, about 200-450 mg,
about 200-400 mg, about 200-350, about 200-300, about 200-250,
about 250-500 mg, about 250-450 mg, about 250-400 mg, about
250-350, about 250-300, about 300-500 mg, about 300-450 mg, about
300-400 mg, about 300-350, about 350-500 mg, about 350-450 mg,
about 350-400 mg, or about 450-500 mg of one or more of Sclerotium
Poriae Cocos, Cortex Moutan Radicis, Rhizoma Alismatis Orientalis,
and/or Anemarrhena Rhizome. In specific embodiments, the
formulation comprises about 25 mg, about 50 mg, about 75 mg, about
100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg,
about 350 mg, about 400 mg, about 450 mg, or about 500 mg of one or
more of Sclerotium Poriae Cocos, Cortex Moutan Radicis, Rhizoma
Alismatis Orientalis, and/or Anemarrhena Rhizome. It will be
appreciated that the amounts above may refer to the amount per
capsule or the amount per daily, weekly or monthly dose.
In other embodiments, the formulation comprises about 15-300 mg,
about 15-270 mg, about 15-250 mg, about 15-240 mg, about 15-210 mg,
about 15-200 mg, about 15-180 mg, about 15-150 mg, about 15-120 mg,
about 15-100 mg, about 15-90 mg, about 15-75 mg, about 15-60 mg,
about 15-50 mg, about 15-45 mg, about 15-30 mg, about 15-25 mg,
about 15-20 mg, about 25-300 mg, about 25-270 mg, about 25-250 mg,
about 25-240 mg, about 25-210 mg, about 25-200 mg, about 25-180 mg,
about 25-150 mg, about 25-120 mg, about 25-90 mg, about 25-100 mg,
about 25-75 mg, about 25-60 mg, about 25-50 mg, about 30-300 mg,
about 30-270 mg about 30-250 mg, about 30-240 mg, about 30-210 mg,
about 30-200 mg, about 30-180 mg, about 30-150 mg, about 30-120 mg,
about 30-100 mg, about 30-90 mg, about 30-75 mg, about 30-60 mg,
about 30-50 mg, about 30-45 mg, about 45-300 mg, about 45-270 mg
about 45-250 mg, about 45-240 mg, about 45-210 mg, about 45-200 mg,
about 45-180 mg, about 45-150 mg, about 45-120 mg, about 45-100 mg,
about 45-90 mg, about 45-75 mg, about 45-60 mg, about 45-50 mg,
about 50-300 mg, about 50-270 mg about 50-250 mg, about 50-240 mg,
about 50-210 mg, about 50-200 mg, about 50-180 mg, about 50-150 mg,
about 50-120 mg, about 50-100 mg, about 50-90 mg, about 50-75 mg,
about 50-60 mg, about 60-300 mg, about 60-270 mg about 60-250 mg,
about 60-240 mg, about 60-210 mg, about 60-200 mg, about 60-180 mg,
about 60-150 mg, about 60-120 mg, about 60-100 mg, about 60-90 mg,
about 60-75 mg, about 75-300 mg, about 75-270 mg about 75-250 mg,
about 75-240 mg, about 75-210 mg, about 75-200 mg, about 75-180 mg,
about 75-150 mg, about 75-120 mg, about 75-100 mg, about 75-90 mg,
about 90-300 mg, about 90-270 mg, about 90-250 mg, about 90-240 mg,
about 90-210 mg, about 90-200 mg, about 90-180 mg, about 90-150 mg,
about 90-120 mg, about 90-100 mg, about 100-300 mg, about 100-250
mg, about 100-200 mg, about 100-150 mg, about 120-300 mg, about
120-270 mg, about 120-250 mg, about 120-240 mg, about 120-210 mg,
about 120-200 mg, about 120-180 mg, about 120-150 mg, about 150-300
mg, about 150-250 mg, about 150-200 mg, about 200-300 mg, about
200-250 mg, about 210-300 mg, about 210-270 mg, about 210-250 mg,
about 120-240 mg, or about 250-300 mg, of Radix Astragali. In
specific embodiments, the formulation comprises about 15 mg, about
20 mg, about 25 mg, about 30 mg, about 45 mg, about 50 mg, about 60
mg, about 75 mg, about 90 mg, about 100 mg, about 120 mg, about 150
mg, about 180 mg, about 200 mg, about 210 mg, about 240 mg, about
250 mg, or about 300 mg of Radix Astragali. It will be appreciated
that the amounts above may refer to the amount per capsule or the
amount per daily, weekly or monthly dose.
In embodiments, the formulation comprises about 20-400 mg, about
20-360 mg, about 20-350 mg, about 20-320 mg, about 20-300 mg, about
20-280 mg, about 20-250 mg, about 20-240 mg, about 20-200 mg, about
20-160 mg, about 20-150 mg, about 20-120 mg, about 20-100 mg, about
20-80 mg, about 20-75 mg, about 20-50 mg, or about 20-40 mg, about
40-400 mg, about 40-360 mg, about 40-350 mg, about 40-320 mg, about
40-300 mg, about 40-280 mg, about 40-250 mg, about 40-240 mg, about
40-200 mg, about 40-160 mg, about 40-150 mg, about 40-120 mg, about
40-100 mg, about 40-80 mg, about 40-75 mg, about 40-50 mg, about
50-400 mg, about 50-350 mg, about 50-300 mg, about 50-250 mg, about
50-200 mg, about 50-150 mg, about 50-100 mg, about 50-75 mg, about
80-400 mg, about 80-360 mg, about 80-350 mg, about 80-320 mg, about
80-300 mg, about 80-280 mg, about 80-250 mg, about 80-240 mg, about
80-200 mg, about 80-160 mg, about 80-150 mg, about 80-120 mg, about
80-100 mg, about 75-400 mg, about 75-350 mg, about 75-300 mg, about
75-250 mg, about 75-200 mg, about 75-150 mg, about 75-100 mg, about
100-400 mg, about 100-350 mg, about 100-300 mg, about 100-250 mg,
about 100-200 mg, about 100-150 mg, about 120-400 mg, about 120-360
mg, about 120-350 mg, about 120-320 mg, about 120-300 mg, about
120-280 mg, about 120-250 mg, about 120-240 mg, about 120-200 mg,
about 120-160 mg, about 120-150 mg, about 150-400 mg, about 150-350
mg, about 150-300 mg, about 150-250 mg, about 150-200 mg, about
160-400 mg, about 160-360 mg, about 160-350 mg, about 160-320 mg,
about 160-300 mg, about 160-280 mg, about 160-250 mg, about 160-240
mg, about 160-200 mg, about 200-400 mg, about 200-350 mg, about
200-300 mg, about 200-250 mg, about 240-400 mg, about 240-360 mg,
about 240-350 mg, about 240-320 mg, about 240-300 mg, about 240-280
mg, about 240-250 mg, about 250-400 mg, about 250-350 mg, about
250-300 mg, about 280-400 mg, about 280-360 mg, about 280-350 mg,
about 280-320 mg, about 280-300 mg, about 300-400 mg, about 300-350
mg, about 320-400 mg, about 320-360 mg, about 320-350 mg, about
350-400 mg, or about 360-400 mg of Atractylodis Macrocephalae
Rhizoma. In specific embodiments, the formulation comprises about
20 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80
mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about
160 mg, about 200 mg, about 240 mg, about 250 mg, about 280 mg,
about 300 mg, about 320 mg, about 350 mg, about 360 mg, or about
400 mg of Atractylodis Macrocephalae Rhizoma. It will be
appreciated that the amounts above may refer to the amount per
capsule or the amount per daily, weekly or monthly dose.
It will be appreciated that the formulation may include any of the
ranges or specific amounts for each of the herbal ingredients as
described above in combination.
Radix Rehmanniae, also known as Shu Di Huang, is a perennial,
flowering herb. It has traditionally been used to treat fever,
anemia, dizziness, palpitations, and uterine bleeding, among
others. Typically, the root is used for treatment. Fructus Corni
Officinalis, also known as Shan Zhu Yu, is a species of dogwood. It
has traditionally been used to treat impotence, chronic lower back
pain, incontinence, and excessive menstrual bleeding, among other
conditions. Typically, the fruit is used for treatment. Radix
Dioscoreae Oppositae, also known as Shan Yao, is used in
traditional medicine to treat lack of appetite and energy, lower
blood sugar and blood pressure, among other conditions. Typically,
the tubers are used for treatment. Sclerotium Poriae Cocos, also
known as Fu Ling, is a fungus traditionally used as a diuretic, and
antibacterial, to lower blood sugar, and to treat gastrointestinal
discomfort. Cortex Moutan Radicis, also known as, Mu Dan Pi, is a
tree peony. It has been traditionally used to treat arthritis,
typhus, nosebleed, fever, etc. Typically, the bark and/or root is
used for treatment. Rhizoma Alismatis Orientalis, also known as Ze
Xie, has traditionally been used as an anti-pyretic, an
antibacterial, to treat hypotension and hypoglycemia, and as a
diuretic, among others. Typically the tubers are used for
treatment. Anemarrhena Rhizome, also known as Zhi Mu, has
traditionally been used for high fever, congestion, dry throat,
coughing, and pneumonia, among others. Typically, the root or
rhizome is used for treatment. Glycyrrhiza uralensis, also known as
Gan Cao, traditionally used to relieve stress and increase
circulation. The root is typically used for treatment. Radix
Astragali, also known as Huang Qi, has traditionally been used to
treat colds, upper respiratory infections, allergies, diabetes, and
high blood pressure, among others. Typically, the root is used for
treatment. Atractylodis Macrocephalae Rhizoma, also known as Bai
Zhu, is traditionally used for spleen disorders and to prevent
miscarriage. Typically, the root or tuber is used for
treatment.
The composition may include one or more excipients or additives
including, but not limited to, fillers or binders, surfactants,
wetting agents, and diluents. The compositions may further include
one or more flavoring agents or sweeteners. Suitable diluents
include water, e.g. deionized water, water for injection (WFI),
filtered water, and purified water. Other suitable diluents include
fruit juices, teas, and milk. Suitable flavorings include fruit
flavorings, mint, including peppermint and spearmint, and cinnamon.
Other suitable additives including food colorings and ethanol. In
some embodiments, the composition comprises a dehydrated extract
combined with one or more diluents, flavoring agents or other
additives. In other embodiments, the composition comprises a
reduced extract in combination with one or more diluents, flavoring
agents or other additives.
The composition formulations may include suitable fillers,
extenders, binders, wetting agents, surfactants, or other
excipients as known in the art. In embodiments, the solid
formulation may include tablets, pills, powders, granules, and
capsules. Where the composition formulations are a powder, the
powder may be formed by any suitable method including, but not
limited to, spray drying or freeze drying. In some embodiments, the
tablets, pills, or capsules may be coated. The coating may be
functional (e.g. modifying release of the composition ingredients)
or non-functional. In an embodiment, the coating provides sustained
release of the herbal formulation. In another embodiment, the
coating provides protection from irritant properties of one of more
of the composition ingredients. Liquid formulations for oral
administration may include suspensions, solutions, emulsions, and
syrups. In one embodiment, the formulation may be added to an oil
including, but not limited to olive oil, vegetable oil, and; or
wheat germ oil. Parenteral formulations include sterilized aqueous
solutions, water-insoluble solutions, suspensions, emulsions, and
suppositories. In other embodiments, the compositions are
formulated as a liquid, oral liposomal formulation, or as
nanoparticles. In embodiments where the formulation or composition
is administered by an oral route, the formulation may be
administered with or after a meal to prevent irritation of the
stomach. In one non limiting embodiment, the formulation or
composition is administered 10 minutes to 1 hour after a meal. In
particular, but not limiting embodiments, the formulation or
composition is administered 10 minutes, 15 minutes, 20 minutes, 30
minutes, 45 minutes, or 60 minutes after a meal.
The compositions or formulations may be administered at a dose
suitable for the indication. One of skill in the art would
appreciate that the dose may depend upon the weight, gender, and
indication. In some embodiments, the composition or formulation is
administered as a dose of about 500-4000 mg of the combined herbal
extracts per day. In non-limiting embodiments, the composition or
formulation is administered as a daily dose of about 500-3500 mg,
500-3000 mg, 500-2500, 500-2000, 500-1500, 500-1000, 1000-4000 mg,
1000-3500 mg, 1000-3000 mg, 1000-2500, 1000-2000, 1000-1500,
1500-4000 mg, 1500-3500 mg, 1500-3000 mg, 1500-2500, 1500-2000,
2000-4000 mg, 2000-3500 mg, 2000-3000 mg, 2000-2500, 2500-4000 mg,
2500-3500 mg, 2500-3000 mg, 3000-4000 mg, 3000-3500 mg, or
3500-4000 mg. In other embodiments, the composition or formulation
is administered as a daily dose of 0.1-10 mg/kg of total herbal
extract.
An extract of an herb or herbal mixture may be prepared by any
conventional methods including, but not limited to, maceration,
percolation, infusion, and heat extraction using one or more
suitable solvents. In embodiments, the composition may be formed by
combining the herb or herbal mixture with one or more solvents for
a time and under conditions suitable for preparing the extract.
After the herb or herbal mixture and solvent have been in contact
for a period of time suitable to form the extract, the solvent and
herb(s) are separated by a suitable method, such as filtering or
centrifugation. The extract can then be further processed, such as
by reducing or dehydrating the extract and/or combining the extract
with further ingredients.
Any suitable solvent as known in the art may be used for
extraction. Suitable solvents for the extraction process
(extraction solvents) include aqueous solvents, water, and aqueous
solutions of ethanol. In an embodiment, heat is applied to the
solvent/herb mixture. In certain embodiments, the solvent and
herbal mixture is heated to boiling for a suitable period of time.
In particular embodiments, the solvent/herb mixture is heated for a
period exceeding about 1 minute. In further embodiments, the
mixture is heated for at least about 1-15 minutes. In other
embodiments, the mixture is heated for at least about 1-10, 1-5,
1-4, 1-3, 5-15, 5-10, or 10-15 minutes. In particular, but not
limiting, embodiments, the mixture is heated for at least about 1,
2, 3, 4, 5, 10, or 15 minutes. It will be appreciated where each
herb is extracted separately, the same or different solvents may be
used for each extraction process.
IV. METHODS OF USE
A. Perimenopause, Menopause, and Postmenopause
The methods, kits, and related formulations described herein are
used for treating, preventing, or ameliorating the symptoms of
perimenopause, menopause, and/or postmenopause for a human subject.
The discussion below is with reference to menopause, but will apply
equally to perimenopause and/or postmenopause symptoms. Menopause
is the 12 months following a woman's last menstrual period.
Menopause is associated with vaginal dryness, hot flashes, night
sweats (especially due to vasomotor instability), sleep disorders,
mood changes, fatigue, weight gain and/or slowed metabolism, among
others. Hormone replacement therapy (HT) by administering estrogens
has been the standard treatment for menopausal symptoms for
decades. However, recent studies have found that the combination of
estrogen and progestin increases a woman's risk for breast cancer,
stroke, colorectal cancer, etc. (Rossouw et al., JAMA, 2002,
288(3):321-333).
In embodiments, the compositions described herein are useful for
treating, preventing or ameliorating vasomotor symptoms of
menopause including hot flashes, hot flushes, and night sweats. In
one particular, but not limiting, embodiment, the compositions are
useful for treating hot flashes. Hot flashes are manifested as an
increase in skin temperature, and are often accompanied by a sudden
onset of sweating on the face, neck and/or chest. Hot flashes may
significantly affect the quality of life. Hot flashes may be
particularly bothersome at night as they can disturb sleep, leading
to fatigue.
The compositions used in the present methods are a combination of
10 botanical agents used in traditional Chinese medicine (TCM) to
treat yin deficiency heat.
As described in Example 1, postmenopausal women treated with a
composition as described herein for 12 weeks experienced a decline
in the frequency and severity of moderate to severe hot flashes.
There were statistically significant reductions in the frequency of
moderate to severe hot flashes from baseline to weeks 4 and 12 as
well as the number of awakenings from sleep due to hot flashes from
baseline to week 12. After 4 and 12 weeks of treatment with the
formulation of Table 2, the median percent decrease in the
frequency of moderate to severe hot flashes was 53.7% (p<0.001)
and 71.2% (p<0.001), respectively. The median percent reduction
in awakenings from sleep due to hot flashes from baseline to week
12 was 53.6% (p<0.001). Observed median percent changes are
presented in FIGS. 2 and 3. The median percent reduction in
moderate to severe hot flashes from baseline to 4 weeks was 53.7%
(p<0.001) and from baseline to 12 weeks was 71.2% (p<0.001).
The median percent reduction in nighttime awakenings from baseline
to week 12 was 53.6% (p<0.001).
The present compositions are a selective estrogen receptor beta
(ER.beta.) agonist that does not exhibit binding affinity for
estrogen receptor alpha (ER.alpha.). As thermoregulatory control
centers of the brain are rich with ER.beta. receptors, selective
ER.beta. agonists may ameliorate hot flashes resulting from
fluctuations in stimulation of these receptors. Moreover,
stimulation of ER.beta. receptors is not associated with the in
vitro and in vivo breast and uterine cell proliferation inherent in
ER.alpha. stimulation. Thus, ER.beta. receptor agonists
theoretically do not carry the risk for breast and uterine cancer
tumor formation inherent in the use of traditional ER.alpha.-based
estrogenic treatments.
As described in Example 3, a composition prepared as described in
Table 2 was shown to selectively activate transcription through
ER.beta.. A single copy of the vitellogenin A2 ERE upstream of the
minimal tk promoter (ERE tk-Luc) was cotransfected into U2OS cells
with an expression vector for human ER.alpha. or ER.beta.. After
transfection, the cells were treated with increasing amounts of
formulation (10, 25, 50, or 100 .mu.g/mL) and luciferase activity
was measured. The cells were treated with 10 nM E2 or 10-100
.mu.g/ml of the formulation for 18 h and luciferase activity was
measured with the results shown in FIGS. 2A-2B. Unlike estradiol,
the formulation did not activate ERE tk-Luc in U2OS cells
transfected with ER.alpha. (see FIG. 2A). However, the formulation
demonstrated activation of ERE tk-Luc in U2OS cells transfected
with ER.beta. (see FIG. 2B). The levels of activation were the same
as for E2 for treatment of 50 and 100 .mu.g/mL. Administration of
25 .mu.g/mL of the formulation was nearly the same as
administration of E2. Further, administration of 10 .mu.g/mL
activated ERE tk-Luc significantly greater than the control.
As described below, there were no significant adverse events after
12 weeks of use. Thus, the compositions described herein are
well-tolerated, safe and effective selective ER.beta. agonist
extracts for the treatment of postmenopausal hot flashes.
B. Reducing Cholesterol Levels
In other embodiments, the compositions described herein are useful
for treating, preventing or ameliorating conditions associated with
high cholesterol levels, hypercholesterolemia. In embodiments, the
compositions are useful for lowering total cholesterol and/or
lowering low density lipoprotein (LDL) levels. Elevated cholesterol
is a major risk factor for coronary heart disease, heart attack and
stroke. High total cholesterol is considered 240 mg/dL or above,
borderline high cholesterol is considered 200-239 mg/dL of blood,
and normal cholesterol levels are less than 180-200 mg/dL. The
total cholesterol measures the high density lipoproteins (HDL), LDL
and a portion of the triglycerides. Recommended ideal levels of LDL
vary based on the subject's risk for heart disease. For subjects at
a very high risk of heart disease, ideal LDL levels are below 70
mg/dL. For subjects at risk for heart disease, ideal LDL levels are
below 100 mg/dL. LDL levels of 100-129 mg/dL are considered near
ideal and 130-159 mg/dL are considered borderline high. LDL levels
of 160-189 mg/dL are considered high, and above 190 mg/DL is
considered very high.
As shown in Example 2, treatment with the formulation for twelve
weeks reduced both the total cholesterol and the LDL levels
significantly from the baseline measurements. The mean total
cholesterol was reduced from 228.0 to 215.9 mg/dL. Thus, the
formulation was effective to reduce the mean total cholesterol
level over 5% from the baseline. The mean LDL level was also
reduced from 136.4 to 125.9 mg/dL. Thus, the formulation was
effective to reduce the mean LDL level over 7% from the
baseline.
C. Weight Loss
In another embodiment, the compositions described herein are useful
for treating, preventing or ameliorating conditions associated with
obesity. In embodiments, the compositions are useful for lowering
or reducing weight and/or lowering a subject's body mass index
(BMI). As shown in Example 2, treatment with the formulation for
twelve weeks reduced both the participant's weight and BMI from the
baseline measurements. The participants' mean weight was reduced
from 73.2 to 72.3. The mean BMI for the participants was also
reduced from 27.2 to 26.8. Thus, the formulation was effective to
reduce both the mean participant weight and the participant
BMI.
As shown in Example 2, the formulations and compositions described
herein are safe for extended use. There were no serious adverse
events, no vaginal bleeding, no cases of endometrial hyperplasia or
cancer and no significant changes in the double wall endometrial
thickness on transvaginal ultrasound after twelve weeks of use.
The formulations and compositions as described herein may be used
for an extended period. For treatment of menopausal symptoms, it
will be appreciated that the formulation or composition may be
administered for as long as the subject is experiencing symptoms.
In an embodiment, the formulation or composition is administered
for 2 weeks to five years or more. In particular embodiments, the
formulation is administered for 2 weeks to 24 months, 2 weeks to 18
months, 2 weeks to 12 months, 2 weeks to 9 months, 2 weeks to 6
months, 2 weeks to 3 months, 2 weeks to 2 months, 2 weeks to 1
month, 4 weeks to 24 months, 4 weeks to 18 months, 4 weeks to 12
months, 4 weeks to 9 months, 4 weeks to 6 months, 4 weeks to 3
months, 4 weeks to 2 months, 6 weeks to 24 months, 6 weeks to 18
months, 6 weeks to 12 months, 6 weeks to 9 months, 6 weeks to 6
months, 6 weeks to 3 months, 6 weeks to 2 months, 8 weeks to 18
months, 8 weeks to 12 months, 8 weeks to 9 months, 8 weeks to 6
months, 8 weeks to 3 months, 8 weeks to 2 months. In some
embodiments, the composition or formulation is administered for a
period of about 4-24 weeks or about 4-52 weeks.
The composition may be administered by any suitable method
including oral or parenteral. It will be appreciated that the
composition may be used in conjunction with other therapies.
V. EXAMPLES
The following examples are illustrative in nature and are in no way
intended to be limiting. Efforts have been made to ensure accuracy
with respect to numbers (e.g., amounts, temperature, etc.) but some
errors and deviations should be accounted for. Unless indicated
otherwise, parts are parts by weight and temperature is in .degree.
C.
A. Abbreviations LDL low density lipoproteins HDL high density
lipoproteins ER.alpha. estrogen receptor alpha ER.beta. estrogen
receptor beta Estradiol E2 RLU relative light units
Example 1
Efficacy Evaluation
A total of 30 postmenopausal women were enrolled to the study and
27 participants completed 12 weeks of treatment with a formulation
as in Table 2:
TABLE-US-00002 TABLE 2 Formulation Percent Weight (mg) Herbal
Extract in Capsule per capsule Radix Rehmanniae 12 60 Fructus Corni
Officinalis 12 60 Radix Dioscoreae Oppositae 12 60 Sclerotium
Poriae Cocos 10 50 Cortex Moutan Radicis 10 50 Rhizoma Alismatis
Orientalis 10 50 Anemarrhena Rhizome 10 50 Glycyrrhiza uralensis 10
30 Radix Astragali 6 30 Atractylodis Macrocephalae 8 40 Rhizoma
The formulation was prepared by obtaining a purified aqueous
extract of the herbs. A spray-dried power was prepared and formed
into capsules. Participants were generally healthy postmenopausal
women 40 to 65 years old who reported at least 5 moderate to severe
hot flashes per day or 35 per week. The majority of the
participants were Caucasian (73.3%). The women were aged 40-65 and
the mean age at baseline was 52.7. At baseline, the average
frequency of moderate to severe hot flashes was 9.0 per day and the
average frequency of awakenings from sleep due to hot flashes was
3.2 per night. All participants experienced a minimum of 5 moderate
to severe hot flashes per day. Baseline demographic and clinical
characteristics are described in Table 3.
TABLE-US-00003 TABLE 3 Baseline and Demographic Characteristics,
Safety Population Formulation 4 g/day Characteristic (N = 30) Age
Mean (SD) 56.6 (4.9) Race White 22 (73.3%) Black/African American 8
(26.7%) Asian 0 American Indian or Alaska Native 0 Native Hawaiian
or Other Pacific Islander 0 Refused to answer 0 Ethnicity Hispanic
or Latino 5 (16.7%) Not Hispanic or Latino 25 (83.3%) Refused to
answer 0 Body Mass Index (kg/m.sup.2) Mean (SD) 27.2 (4.5) Length
of Time Experiencing Hot Flashes (years) Mean (SD) 8.0 (4.7) Time
Since Menopause, % Less than 24 months 4 (13.3%) 24 months or more
26 (86.7%) Screening Endometrial Thickness on TVUS (mm) n 21 Mean
(SD) 2.03 (1.0) Prior Estrogen User, % 3 (10.0%) Both Ovaries
Removed with or without 7 (23.3%) hysterectomy, % Hysterectomy and
FSH >40 mIU/ml, % 9 (30.0%)
To establish a baseline, all participants had a physical
examination, including blood pressure and heart rate, a breast and
pelvic exam, laboratory tests and, in women with an intact uterus,
a transvaginal ultrasound to measure endometrial double wall
thickness was completed.
The formulation was administered as 4 500 mg capsules orally, twice
a day, about 30 minutes after meals. The study treatment was 4
g/day (total herbs) for 12 weeks.
Hot flash frequency and severity were recorded on a paper diary
model. The 7-day diary was completed prior to randomization and
during weeks 4, 8 and 12 on study medication. For each hot flash,
severity was rated as 1 (mild), 2 (moderate) or 3 (severe). In
addition, participants noted on the diary if the hot flash awoke
them from sleep. Hot flash diaries were reviewed and collected by
the study coordinator at the week 5 visit and at week 12 (study
termination). The primary efficacy outcome was median percent
change in moderate to severe hot flashes from baseline to 12 weeks
of treatment. Secondary endpoints included the median percent
change in frequency of moderate to severe hot flashes from baseline
to 4 weeks of treatment and median percent change in the frequency
of hot flashes that awoke participants from sleep from baseline to
12 weeks of treatment.
There were statistically significant reductions in the frequency of
moderate to severe hot flashes from baseline to weeks 4 and 12 as
well as the number of awakenings from sleep due to hot flashes from
baseline to week 12. After 4 and 12 weeks of treatment with the
formulation, the median percent decrease in the frequency of
moderate to severe hot flashes was 53.7% (p<0.001) and 71.2%
(p<0.001), respectively. The median percent reduction in
awakenings from sleep due to hot flashes from baseline to week 12
was 53.6% (p<0.001). Observed median percent changes are
presented in FIGS. 2 and 3.
Example 2
Safety Evaluation
To evaluate safety, individual treatment emergent adverse events
(TEAEs) events were captured at weeks 2, 5, 8, 12 and 14.
Participants were also advised to contact the clinical site by
phone or schedule an in-person clinic visit at any time during the
trial to report an adverse event. Physical examinations with vital
signs were completed at baseline and week 12. All laboratory tests
completed at baseline and at study termination, including complete
blood counts, chemistry panels and urinalyses were processed by
Enzo Central Laboratories. Endometrial safety was assessed by
comparing baseline transvaginal ultrasound (TVUS) results for
double wall endometrial thickness to the TVUS results at study
termination. Diagnostic endometrial biopsies were performed during
the study if a participant reported vaginal spotting, vaginal
bleeding or if the final endometrial double wall thickness measured
by TVUS was over 8 mm. Treatment emergent adverse events were
classified using the Medical Dictionary for Regulatory Activities
(MedDRA) system.
The safety population included all 30 postmenopausal women enrolled
to the study. During the study, there were no serious adverse
events, no cases of abnormal vaginal bleeding, no laboratory
abnormalities and no cases of endometrial double wall thickness
>8 mm on transvaginal ultrasound while on treatment or at study
termination. Three participants (10%) discontinued study treatment
due to rash, stomach pains and influenza. The first 2 AEs were
coded as related to study treatment. A fourth participant reported
abdominal bloating which was coded as related to study treatment
and a fifth participant reported experiencing bloody exudate from
her nipple. The nipple discharge could not be repeated during a
follow up visit with a surgeon and a repeat mammogram showed no
changes from baseline or any evidence of suspicious lesions.
Of the 30 participants in the study, 21 or 70% (had a uterus. All
women with an intact uterus had a transvaginal ultrasound at
baseline and all had this test repeated at the end of the trial.
Mean endometrial thickness was 2.03 mm at baseline and 2.38 at 12
weeks; there were no differences mean endometrial thickness
(p=0.16).
TABLE-US-00004 TABLE 4 Number (%) of participants reporting
treatment emergent adverse events Formulation 4 g/day MedDRA SOC
Adverse Event N (%) Gastrointestinal Abdominal distension/bloating
1 (3.3%) Disorders Gastrointestinal pain 1 (3.3%) Infections and
Influenza 1 (3.3%) Infestations Skin and Rash 1 (3.3%) Subcutaneous
Disorders
Treatment adherence was measured by diaries at the week 5 and week
12/early termination visits. Table 4 is a summary of adherence with
study medication by patient reported diaries. The mean treatment
compliance was 91.1% (range 83%-100%).
There was a statistically significant decrease in BMI, total
cholesterol and LDL cholesterol.
TABLE-US-00005 TABLE 5 Weight, BMI, Blood Pressure and Cholesterol
End of Study Baseline P-value Mean SD N Mean D (Paired t-test)
Weight 0 73.2 11.9 29 72.3 1.9 0.0570 BMI 0 27.2 4.5 29 26.8 .5
0.0324 Diastolic 0 79.6 6.3 29 79.3 .8 0.6766 Blood Pressure
Systolic 0 118.9 10.0 29 111.6 .5 0.2163 Blood Pressure Total 0
228.0 40.8 29 215.9 9.6 0.0098 Cholesterol Triglycerides 0 124.5
78.6 29 140.0 19.8 0.2563 HDL 0 66.3 19.1 29 63.7 8.8 0.2102 LDL 0
136.4 35.1 29 125.9 3.5 0.0090
Example 3
Estrogen Receptor Selectivity
It is well established that the effects of estrogens on hot flashes
are mediated by estrogen receptors. ER.alpha. and ER.beta. are both
present in the brain. To determine if the present compositions can
regulate ER.alpha. and/or ER.beta., human U2OS osteosarcoma cells
were co-transfected with a classical estrogen response element
(ERE) upstream of a minimal thymidine kinase (tk) promoter
(ERE-tk-Luc) and expression vectors for human ER.alpha. and
ER.beta.. An herbal extract composition as in Table 2 produced a
dose-dependent activation of ERE-tk-Luc with ER.beta. (FIG. 1B),
whereas no significant activation was observed with ER.alpha. (FIG.
1A). These results demonstrate that the present compositions are
ER.beta.-selective agonists.
While a number of exemplary aspects and embodiments have been
discussed above, those of skill in the art will recognize certain
modifications, permutations, additions and sub-combinations
thereof. It is therefore intended that the following appended
claims and claims hereafter introduced are interpreted to include
all such modifications, permutations, additions and
sub-combinations as are within their true spirit and scope.
All patents, patent applications, and publications mentioned herein
are hereby incorporated by reference in their entireties. However,
where a patent, patent application, or publication containing
express definitions is incorporated by reference, those express
definitions should be understood to apply to the incorporated
patent, patent application, or publication in which they are found,
and not necessarily to the text of this application, in particular
the claims of this application, in which instance, the definitions
provided herein are meant to supersede.
* * * * *
References